Sterilizable transfer or storage device for medicaments, drugs and vaccines

ABSTRACT

A medical transfer or storage device for delivery or storage of a medicament, drug or vaccine, wherein a first component, preferably the major component, is formed of a cyclic olefin polymer, and a second component in contact with the first component is formed of a second polymer which does not chemically interact with the cyclic olefin polymeric component at elevated temperatures, including sterilization. More specifically, the relative energy distance Ra/Ro of the polymer selected for the second component relative to the cyclic olefin polymer is greater than 0.75 and the molecular weight of the second polymer is at least 5,000 to prevent adhesion of the second component to the cyclic olefin component and stress cracking at elevated temperatures. The most preferred embodiment is a syringe assembly having a cyclic olefin polymeric barrel and a resilient stopper formed of the second polymer.

CROSS-REFERENCE TO RELATED APPLICATION

This patent application is a divisional of U.S. patent application Ser.No. 09/835,446, filed on Apr. 16, 2001 now U.S. Pat. No. 6,595,961currently allowed and pending.

BACKGROUND OF THE INVENTION

The present invention relates to a transfer or storage deviceparticularly, but not exclusively, for delivery or storage of amedicament, drug or vaccine, such as a syringe, transfer set, injectiondevice or vial, wherein the major component of the delivery or storagedevice is preferably formed of a cyclic olefin polymer.

The development of cyclic olefin polymers has suggested the use of suchpolymers for manufacture of medical devices because medical devicesformed of such polymers are transparent, exhibit excellent chemicalresistance and may be sterilized by autoclaving or the like withoutdamage. See European patent application EP 436,732A2. However, it hasbeen found that medical devices, such as syringes, transfer devices andvials formed of cyclic olefin polymers are subject to stress cracking,particularly during or following sterilization, limiting the use of suchpolymers for medical devices. Stress cracking is defined as the crazingor cracking that may occur when a plastic under tensile stress isexposed to aggressive chemicals. The potential for environmental stresscracking is of major concern when plastics are used in medical devicesbecause stress cracking may compromise the mechanical integrity of thedevice and contaminate the medicament, drug or vaccine transferredthrough or stored within the medical device.

Another problem with the use of cyclic olefin polymers for medicaldevices, such as storage or delivery devices, is adhesion of manypolymers to cyclic olefin polymers following sterilization at elevatedtemperatures, such as autoclaving. For example, a syringe assemblyincludes a plunger having a stopper which withdraws fluid through thebarrel tip when the stopper is withdrawn and drives fluid through thebarrel tip when the stopper is advanced. Syringe stoppers areconventionally formed of a resilient synthetic rubber, such asbromo-butyl rubber, having an initial diameter greater than the internaldiameter of the tubular syringe body, providing a good seal. However,when the syringe assembly is heated to the sterilization temperature ofthe cyclic olefin polymer and the bromo-butyl rubber stopper, thestopper firmly adheres to the cyclic olefin polymer syringe barrelmaking it difficult, if not impossible, to telescopically move theplunger through the tubular syringe barrel.

A similar problem exists with removable syringe tip caps or tip shieldswhich firmly adhere or fuse to the syringe tip following heating to thesterilization temperature of the assembly. The tip caps and tip shieldsformed of certain polymers cannot be removed from the syringe followingheating. It has also been found by the assignee of this patentapplication that this adhesion between various polymers and cyclicolefin polymeric transfer and storage devices following heating may alsopromote stress cracking. Thus, the use of cyclic olefin polymers formedical transfer and storage devices has been severely limited by theseproblems.

The sterilizable transfer or storage device and method of this inventionsolves these problems by selecting a polymer for the component incontact with the cyclic olefin polymer transfer or storage device whichdoes not interact with the cyclic olefin polymer, even at elevatedtemperatures, thus permitting the use of cyclic olefin polymers formedical transfer and storage devices of the type described herein.

SUMMARY OF THE INVENTION

As set forth above, the present invention relates to sterilizablemedical transfer or storage devices, such as syringes, transfer sets,vials, injection devices and the like, wherein a component, generallythe major component, is formed of a cyclic olefin polymer and the deviceincludes a second component formed of a second polymer in contact withthe cyclic olefin component. More specifically, the present inventionrelates to the selection of the polymeric material for the secondcomponent which assures that the second component does not chemicallyinteract with, dissolve or attack the cyclic olefin polymeric componentor cause stress cracking, particularly at the elevated temperaturesrequired for sterilization.

The polymers selected for the second member or component of thesterilizable transfer or storage device and method of this invention isbased upon solubility parameters and cohesion properties explained byCharles Hansen in “The Three Dimensional Solubility Parameter andSolvent Diffusion Coefficient” by Charles M. Hansen, Copenhagen DanishTechnical Press (1967) and the Hansen values for polymers are reportedin Chapter 14 of “The CRC Handbook and Solubility Parameters andCohesion Parameters,” Edited by Allan F. M. Barton (1999). Each materialis defined by three points in 3D space and these three points are knownas the Hansen Solubility Parameters (HSP). The Hansen SolubilityParameters may be defined as follows.

The Hansen solubility region consists of a point in 3D space defined bya non-polar dispersion interaction (Delta-D) axis, a polar or dipoleinteraction (Delta-P) axis and hydrogen bonding interaction (Delta-H)axis. From the location (Delta-D, Delta-P, Delta-H), a radius isprojected to form a sphere which encompasses the region where liquidshaving HSP parameters within the inside of this sphere are generally the“attacking” the material in question, and liquids outside of the sphereare generally not attacking the material in question (See also“Environmental Stress Cracking In Plastics,” Hansen and Just,Pharmaceutical and Medical Packaging (1999), Vol.9, 7.1 to 7.7, ISBN87-89753-26-7. Hansen also noted that higher stress/temperature levelswill enlarge the sphere (increase the radius) as well as the size andshape of the liquid molecules. Generally, the larger the molecule, theharder it is for the molecule to attack the material in question. Thus,as discussed further below, the molecular weights of the components arealso important to prevent interaction. The assignee of this applicationhas noted material interactions under ambient conditions, but materialinteraction is found more frequently at elevated temperatures, such asduring autoclaving and annealing. As set forth above, however, theproblems associated with material interaction between cyclic olefinpolymers and the polymers conventionally used for components of medicaldevices has severely limited the use of cyclic olefin polymers inmedical transfer and storage devices.

The distance between the HSP coordinate of polymer A to HSP coordinatesof another material (liquid or Polymer B) is defined as Ra. The radiusof the Polymer A sphere is defined as Ro. Ra/Ro is now defined by Hansenas the Relative Energy Distance (RED). Hansen reports that if Ra/Ro isless than 1, the two materials may stress crack or dissolve each other.If Ra/Ro is greater than or equal to 1, the materials do not have anaffinity to one another under standard conditions. Ro is determinedthrough experimentation described by Hansen, and the 3D distance, Ra, isdefined by the equation:

(Ra)² =4(Delta-D₁−Delta-D₂)²+(Delta-P₁−Delta-P₂)²+(Delta-H₁−Delta-H₂)²

1=polymer

2=liquid (2^(nd) solid in this disclosure)

and

RED=Relative Energy Distance=Ra/Ro

Ra/Ro is inside the polymer sphere if it is less than 1

Ra/Ro is on the surface of the sphere if it is 1

Ra/Ro is outside the polymer sphere if it is greater than 1.

For Ticona Topas® cyclic olefin copolymers, the Hansen SolubilityParameters have been reported by Hansen to be:

Delta-D=18.0, Delta-P=3.0 and Delta-H=2.0 and Ro=5.0

For Ticona Topas, a cyclic olefin, which has seen cracking the HansenSolubility Parameters have been reported by Hansen to be:

Delta-D=17.3, Delta-P=3.1 and Delta-H=2.1 and Ro=6.4.

The stress cracked Ticona resin has a bigger sphere, more easilyattacked than non-stress cracked Topas material.

Thus, the larger the Hansen solubility difference between two polymers,the less likely the polymers will destructively interact.Experimentation by the applicant has shown that this difference isparticularly important in the use of cyclic olefin polymers in medicaldevices which must be sterilized before use. As stated above, Hansen hasalso found that an increase in temperature will enlarge the sphere ofinteraction. For example, it has been found by the applicant that asyringe stopper will have a lower breakout force and a lower sustainingforce when the relative energy distance Ra/Ro is increased to greaterthan 0.75 or most preferably equal to or greater than one; whichprevents adhesion of the plunger stopper to a cyclic olefin polymerbarrel and reduced stress cracking of the barrel at elevatedtemperatures, such as the sterilization temperature. For example, it hasbeen found by the applicant that a bromo-butyl rubber stopper in asyringe formed of a cyclic olefin polymer has a breakloose force ofapproximately 4.5 kg., whereas a styrene-butadiene rubber stopper has abreakout force of only approximately 1.0 kg. The applicant hasdetermined that the relative energy distance Ra/Ro of butyl rubberrelative to a conventional cyclic olefin polymer is 0.3, whereas therelative energy distance Ra/Ro of styrene-butadiene rubber compared tothe cyclic olefin polymer is about 1.0. Further, it has been found thata bromo-butyl rubber stopper in a cyclic olefin polymer syringe barrelwill fuse to the barrel following autoclaving, whereas astyrene-butadiene rubber stopper in a cyclic olefin polymer syringebarrel will not be adversely affected by autoclaving. Furtherexperimentation has shown that where the relative energy distance Ra/Roof the polymer used for the plunger relative to a syringe barrel formedof a cyclic olefin polymer is greater than about 0.75, the plunger willnot adversely adhere to the barrel or cause stress cracking of thebarrel.

The sterilizable storage device of this invention thus comprises a firstmember, preferably a major component, such as a syringe barrel, transferset, vial, cartridge or the like formed from a cyclic olefin polymer anda second member or component, such as a syringe stopper, tip cap or tipshield formed of a second polymer or a composite or laminate or coatingwherein the interface layer is formed of the second polymer, wherein therelative energy distance Ra/Ro of the second polymer relative to thecyclic olefin polymer is greater than 0.75 or more preferably equal toor greater than one which prevents adhesion of the second component tothe first component and stress cracking. A high molecular weight/molarvolume of the non-cycling olefin polymer also prevents the non-cyclicolefin polymer from attacking the cyclic olefin. In the most preferredembodiment, the cyclic olefin component has a molecular weight of atleast 20,000 and the non-cyclic olefin component has a molecular weightof at least 5,000 or more preferably greater than 7,500.

A preferred embodiment of this invention is a syringe barrel formed of acyclic olefin polymer and a plunger stopper formed of a second polymerwhich has the requisite relative energy distance. Another preferredembodiment is a syringe barrel formed of a cyclic olefin polymer and atip cap or tip shield formed of a second polymer, as described. As setforth above, the syringe stopper, for example, may be formed of astyrene-butadiene or a fluorocarbon polymer. However, it is believedthat other polymers, polymer/compositions would be suitable for thesecond polymer provided the relative energy distance Ra/Ro of the secondpolymer relative to the cyclic olefin polymer is greater than 0.75. Inthe most preferred embodiment, the relative energy distance Ra/Ro of thesecond polymer is equal to or greater than 0.8 or most preferablygreater than 1.

Thus, the most preferred method of making a sterilized syringe assembly,for example, comprises the steps of forming a syringe body from a cyclicolefin polymer, forming a plunger stopper from a second polymer, whereinthe relative energy distance Ra/Ro of said second polymer relative tosaid cyclic olefin polymer of the syringe body is greater than 0.75. Theplunger is then telescopically received in the tubular syringe barrelwith the plunger stopper in contact with the syringe barrel. Finally,the syringe barrel and plunger stopper are heated to the sterilizationtemperature of the syringe barrel and plunger stopper. The method ofmaking a sterilizable syringe assembly may also include forming a tipcap or tip shield from a third polymer, which may be identical to ordifferent from the second polymer, and wherein the relative energydistance Ra/Ro of the third polymer relative to the cyclic olefinpolymer is greater than 0.75 and assembling the tip cap or tip shield onthe syringe body before heating.

Thus, the sterilizable transfer or storage device and method of thisinvention solves the problems associated with using a cyclic olefinpolymer for such medical devices and permits sterilization of theassembly without stress cracking or adhesion of the components. Otheradvantages and meritorious features of this invention will be more fullyunderstood from the following description of the preferred embodiments,the appended claims and the drawings, a brief description of whichfollows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded view of a syringe assembly illustrating onepreferred embodiment of this invention;

FIG. 2 is a side cross-sectional view of the syringe assembly shown inFIG. 1 following assembly;

FIG. 3 is a side cross-sectional view of the syringe assembly shown inFIG. 2 during sterilization;

FIG. 4 is an enlarged partial side cross-sectional view of FIG. 2; and

FIG. 5 is a side cross-sectional view of another embodiment of a syringeassembly of this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As described above, this invention relates to a sterilizable medicaltransfer or storage device for delivery or storage of a medicament, drugor vaccine, wherein a component of the device, generally the majorcomponent, is formed of a cyclic olefin polymer. As used herein, theterm “cyclic olefin polymer” is intended to broadly cover the family ofcyclic olefin polymers/copolymers, including bridged cyclic olefinpolymers as disclosed, for example, in the patents of Nippon Zeon Co.,Ltd., including U.S. Pat. No. 5,561,208 and European patent publicationEP 920 989 A2. As will be understood, however, cyclic olefin polymersare available from a variety of sources including Dow Chemical Companywhich makes a polycyclohexylenethylene and Ticon, a division of CelaneseAG (formerly Hoechst Technical Polymers), which makes a cycloolefincopolymer under the tradename “Topas”. A suitable cyclic olefin polymerfor the sterilizable transfer or storage device and method of thisinvention is available from Nippon Zeon Co., Ltd. under the trade nameZeonex™. As set forth above, cyclic olefin polymers have characteristicsand properties which strongly recommend the use of such polymers formedical applications, including excellent transparency, chemicalresistance, etc. However, such use has been inhibited by chemicalinteraction resulting in adhesion, dissolving or fusion with otherpolymers typically used for components of such medical devices andstress cracking, particularly at the elevated temperatures required forsterilization, which is generally between 120 to 125 C for about 50minutes.

The sterilizable transfer or storage device and method of this inventionsolves these problems by selection of the polymer for the components ofthe device in contact with the cyclic olefin polymeric component whichavoids chemical interaction with the cyclic olefin polymeric componentbased upon the Hansen relative energy distance Ra/Ro discussed in detailabove. More specifically, the sterilizable transfer or storage device ofthis invention comprises a first member formed of a cyclic olefinpolymer, which is preferably the major component of the device such as asyringe barrel, transfer set, vial or the like. The transfer or storagedevice further includes a second member or component in contact with thefirst member formed of a second polymer, wherein the relative energydistance Ra/Ro of the second polymer relative to the cyclic olefinpolymer is at least 0.75 to prevent adhesion of the second member to thefirst member and stress cracking of the cyclic olefin polymer member atelevated temperatures, including sterilization, annealing, etc. Althoughthe sterilizable transfer or storage device and method of this inventionhas several applications, particularly in regard to medical devices, theinvention will now be described in regard to a syringe for delivery orstorage of a medicament, drug or vaccine, as follows.

FIGS. 1 to 4 illustrate one embodiment of a syringe assembly 20 suitablefor the sterilizable storage or delivery device and method of thisinvention. The syringe assembly 20 shown in FIGS. 1 to 4 includes agenerally tubular barrel 24 and a plunger 26 having a resilient stopper28 telescopically received in the generally tubular barrel 24 as bestshown in FIG. 2. In this embodiment, the syringe assembly 20 furtherincludes a tip cap 30 threadably received on the reduced diameter tipportion 32 of the barrel. The syringe barrel 24 may also include anintegral flange portion 34, which provides a finger grip, and theplunger may also include a flange 36 which assists the healthcare workerto withdraw or advance the plunger 26 in the barrel 24. In thisembodiment of the syringe assembly 20, the resilient stopper 28 includesa plurality of radial rib portions 38 which contact the internal surface40 of the barrel 24, providing a seal during withdrawal and advance ofthe plunger 26 in the barrel 24.

As will be understood by those skilled in this art, a syringe assemblyof this type may be utilized for storage and delivery of medicaments,drugs or vaccines. That is, the syringe may be prefilled to store amedicament, drug or vaccine and the syringe assembly may then beutilized to transfer a medicament, drug or vaccine to a patient. The tipcap 30 may be threadably removed from the barrel tip 32 and a needlecannula (not shown) may be threadably assembled on the tip 32 fordelivery of a medicament, drug or vaccine to a patient by advancing theplunger 26. In the preferred embodiments of this invention, the barrel24 is formed from a cyclic olefin polymer and the polymer used to formthe stopper 28 and tip cap 30 is selected to avoid a chemicalinteraction between the polymers selected for these components and thecyclic olefin polymeric barrel 24. More specifically, the relativeenergy distance Ra/Ro of the polymers selected for the stopper 28 andtip cap 30 relative to the cyclic olefin polymer of the barrel 24 isgreater than 0.75 or more preferably equal to or greater than 1 toprevent adhesion or fusion of the stopper 28 and the tip cap 30 to thebarrel 24 and stress cracking of the barrel at elevated temperaturesincluding sterilization. Experimentation has shown that where therelative energy distance Ra/Ro is less than about 0.75, the portions ofthe stopper 28 and the tip cap 30 in contact with the barrel 24 willfuse to the barrel during autoclaving. As shown in FIG. 4 and describedabove, the stopper 28 includes a plurality of radial rib portions 38which must resiliently contact the internal surface 40 of the barrel 24to provide a seal. During autoclaving, these rib portions 38 will fuseto the internal surface 40 of the barrel where the relative energydistance Ra/Ro of the polymer selected for the plunger relative to thecyclic olefin polymer of the barrel is less than about 0.75 and resultin stress cracking of the barrel. Similarly, the tip cap 30 will fuse tothe tip 32 during autoclaving where the polymers selected for the tipcap 30 relative to the cyclic olefin polymer barrel 24 is less thanabout 0.75. In the most preferred embodiments, this ratio is greaterthan 1.

Thus, polymers including butyl rubber, chlorobutyl rubber, nitrilebutadiene, isobutylene/isoprene and isoprene elastomers having arelative energy distance Ra/Ro of about 0.5 will fuse to a cyclic olefinpolymer barrel at elevated temperatures including autoclaving, whereasstyrene-butadiene and fluorocarbon polymers including Teflon having arelative energy distance Ra/Ro of about 1 or greater will not chemicallyinteract with a cyclic olefin polymer barrel and are thereforeacceptable as the second component of the syringe assembly 20, such asthe stopper 28 and the tip cap 30. As will be understood, the secondcomponent may be formed of any suitable material provided the interfaceof the second component, which may be formed by coating, lamination,etc. is formed of a polymer as described herein. Although fluorocarbonpolymers are acceptable, such polymers are relatively expensive and aretherefore not included in the most preferred polymers for the secondcomponent.

The method of making a sterilizable syringe assembly of this inventiontherefore includes forming a generally tubular syringe barrel 24 from acyclic olefin polymer; forming a plunger stopper 28 from a secondpolymer, wherein the relative energy distance Ra/Ro of the secondpolymer to the cyclic olefin polymer of the syringe barrel is greaterthan 0.75 as shown in FIG. 1; telescopically receiving the plungerstopper 28 in the generally tubular barrel 24 as shown in FIG. 2 withthe plunger stopper 28 in contact with an inside surface 40 of thegenerally tubular barrel as shown in FIG. 4; and then heating thesyringe barrel and plunger stopper to the sterilization temperature ofthe barrel and plunger stopper as shown in FIG. 3. Similarly, where thesyringe assembly 20 includes a tip cap as shown at 30, the methodfurther includes forming the tip cap 30 of a third polymer, which may beidentical to or different from the polymer selected for the stopper 28,wherein the relative energy distance Ra/Ro of the polymer selected forthe tip cap relative to the cyclic olefin polymer of the barrel 24 isgreater than 0.75, assembling the tip cap on the syringe barrel asdescribed and then heating the assembly to the sterilization temperatureof the assembly.

FIG. 5 illustrates an alternative embodiment of a syringe assembly 120which includes a generally tubular barrel 124, a plunger 126 having astopper 128 and a tip shield 130 which is received on the reduceddiameter tip portion 132 of the barrel. The tip shield 130 encloses aneedle cannula assembly 131 secured to the end of the reduced diameterbarrel portion 132, as shown. As described above, the barrel 124 mayalso include a finger grip 134 and the plunger may include a flange 136.The stopper 128 may also include a plurality of radial rib portions 138which sealingly engage the internal surface 140 of the barrel 124. Thesyringe assembly 120 further includes a label 142 which is affixed tothe external surface of the barrel 124. Thus, in this embodiment, theplunger stopper 128, tip shield 130 and label 142 contact the barrel124, which is preferably formed of a cyclic olefin polymer as describedabove. In this embodiment, the stopper 128, tip shield 120 and label 142are all formed of polymers wherein the relative energy distance Ra/Ro ofsuch polymers relative to the cyclic olefin polymeric barrel 124 isgreater than 0.75 to prevent adhesion of the stopper 128 and tip cap 130to the barrel 124. Further, the use of a polymer for the label 142having a relative energy distance Ra/Ro of such polymer relative to thecyclic olefin polymer barrel 124 greater than about 0.75 prevents stresscracking of the barrel at elevated temperatures. As will be understood,however, the label 142 may include a polymeric layer or polymericadhesive in contact with the cyclic olefin barrel 124, wherein the outerlayer is formed of a different material, including paper or foil. Themethod of forming the syringe assembly 120 may otherwise be identical tothe method of forming the syringe assembly 20 described above.

Having described two preferred embodiments of the sterilizable transferor storage device and method of this invention, it will be understoodthat various modifications may be made to the disclosed storage andtransfer device and method of this invention within the purview of theappended claims. For example, the medical device of this invention maybe a transfer set or vial wherein a first component is formed of acyclic olefin polymer and a second component is formed from a secondpolymer, wherein the relative energy distance Ra/Ro of the secondcomponent relative to the cyclic olefin polymeric component is greaterthan 0.75 or more preferably equal to or greater than 1. As a furtherembodiment of the sterilizable transfer or storage device of thisinvention, a vial is formed of a cyclic olefin polymer and the stopperis formed of a second polymer, wherein the relative energy distanceRa/Ro of the second polymer selected for the stopper relative to thecyclic olefin polymeric vial is greater than 0.75 to prevent adhesion ofthe stopper to the vial and stress cracking of the vial at elevatedtemperatures, including autoclaving.

What is claimed is:
 1. A method of making a sterilized syringe assemblycomprising the following steps: forming a generally tubular syringebarrel from a cyclic olefin polymer; forming a plunger stopper from asecond polymer, wherein the relative energy distance Ra/Ro of saidsecond polymer relative to said cyclic olefin polymer of said syringebarrel is greater than 0.75; telescopically receiving said plungerstopper in said generally tubular syringe barrel with said plungerstopper in contact with an inside surface of said generally tubularsyringe barrel; and heating said syringe barrel and said plunger stopperto the sterilization temperature of said syringe barrel and plungerstopper.
 2. The method as recited by claim 1, wherein said methodfurther comprises: forming a tip cap or tip shield from a third polymer,wherein the relative energy distance Ra/Ro of said third polymerrelative to said cyclic olefin polymer is greater than 0.75 to preventadhesion of said tip cap or tip shield to said syringe body and stresscracking of said syringe body at elevated temperatures; and assemblingsaid tip cap or tip shield on said syringe barrel before said step ofheating said syringe barrel.
 3. The method as recited by claim 1,wherein said step of forming a generally tubular syringe barrelcomprises forming a generally tubular syringe barrel having a molecularweight of at least 5,000.
 4. The method as recited by claim 1, whereinsaid step of forming a plunger stopper comprises forming a plungerstopper of a polymer selected from the group consisting essentially ofstyrene butadiene and a fluorocarbon polymer.
 5. The method as recitedby claim 2, wherein said step of forming a tip cap or tip shield from athird polymer comprises forming a tip cap or tip shield from a thirdpolymer formed of a styrene butadiene polymer and having a surfaceplaceable in contact with said syringe barrel.
 6. The method as recitedby claim 5, wherein said third polymer is the same as said secondpolymer.